Gastritis, gastric ulcer, duodenal ulcer and reflux gastritis comprise common disorders of the alimentary tract. The etiology behind these disorders is not fully clear but it is believed that mental stress may be a contributing factor. Other factors that may be of importance are dietary factors, too large consumption of coffee, tobacco and alcohol, certain kinds of medication, and anatomical or functional anomalies. Recently it has been demonstrated that a bacteria (Heliobacter pilori) is associated with ulcer formation in the ventricle but a clear-cut causative relationship between this bacteria and ulcer formation in the ventricle or duodenum so far has not been established.
Generally, it is believed that the parasympathetic nervous system is important for normal functioning of the ventricle and parasympathectomy by selectively cutting the cholinergic nerve fibres from the regal nerve (selective vagotomy) has been used as a modality of treatment of gastric or duodenal ulcer. The acidity of the gastric juice is due mainly to hydrochloric acid (HCl) secreted by the parietal cells in the gastric mucosa. The main function of HCl is to acidify the gastric juice enough to enable acid hydrolysis of proteins and to activate pepsinogen secreted by the gastric mucosa to pepsin which catalyses the hydrolysis of proteins in the stomach. Too much secretion of HCl is believed to predispose to gastric and particularly duodenal ulcer. The secretion of HCl from the parietal cells is physiologically controlled in a complex way. The parietal cells are receptive to at least four different autacoids, namely acetylcholine, gastrin, histamine and prostaglandins. Particularly prostaglandins of the E type have been shown negatively to affect secretion of HCl. Acetylcholine, gastrin and histamine enhance the secretion of HCl, whereas prostaglandins inhibit or decrease the secretion of HCl. In a particular disease, the Zollinger-Ellison Syndrome, a tumour producing gastrin causes a marked increase in the secretion of gastric acid.
In addition to secretion of HCl, secretion of bicarbonate (HCO.sub.3.sup.-) by the gastric mucosa and particularly by the duodenal mucosa is considered important for protecting the local tissue from damage by the gastric juice. Prostaglandins stimulate this secretion of HCO.sub.3.sup.-, e.g. in the duodenal mucosa. Prostaglandins, particularly of the E type also effectively stimulate mucus formation. Increased secretion of mucus may have an important protective effect on the mucous membrane in the ventricle as well as in the duodenum.
Gastric ulcers, duodenal ulcers and gastritis are usually treated with antacids (neutralizing agent) and/or antihistamines. Particularly H2 blockers such as cimetidine and ranitidine are effective antiulcer medications Inhibitors of gastrin receptors such as proglumide are also to some extent employed. Recently, the utilization of H.sup.+ /K.sup.+ -ATPase inhibitors has been employed to block gastric secretion. A drug with such activity is omeprazole. Generally, cholinolytic agents are not used but selective vagotomy is employed in some cases. Recently, prostaglandins particularly of the E type, e.g. 16-hydroxy-16-methyl-PGE.sub.1 -methyl ester (Misoprostol) have been demonstrated to be effective. Prostaglandins have been found to be particularly advantageous when used prophylactically to prevent formation of gastric or duodenal ulcer during therapy with anti-inflammatory drugs, such as aspirin, indomethacin and like agents. Common for these agents is that they inhibit the cyclooxygenase enzyme in the biosynthesis of prostaglandins.
The most likely mechanisms of action of prostaglandins to protect the mucous membrane of the ventricle and duodenum are increased formation of mucus, increased secretion of HCO.sub.3.sup.-, as well as an antisecretory effect of prostaglandins on HCl. However, the latter two mechanisms require relatively large amounts of prostaglandins to be present and since clinically such concentrations are not achieved it is generally believed that the main mechanism of exogenous prostaglandins to protect the ventricle and duodenum from ulcer formation is increased mucus formation. A direct cytoprotective effect is also possible. Increased mucus formation is also beneficial with regard to healing of already established ulcers. Endogenous prostaglandins, physiologically released, may also have an important anti-secretory effect as well as an effect on bicarbonate transport.
Prostaglandins of the E type have been found to increase mucus formation in the stomach. Prostaglandins of the E type also markedly increase the blood flow in the ventricle.
A disadvantage of prostaglandin treatment, however, is the relatively frequent occurrence of gastrointestinal side effects. Typically prostaglandins of the E type cause diarrhea. Abdominal pain, dyspepsia, flatulence and nausea may also occur during treatment with prostaglandins. Of these side effects diarrhea and abdominal pain seem to be the most disturbing side effect not infrequently resulting in interruption of the treatment with prostaglandins which seem to be about as effective as H2 blockers in the treatment of gastric and duodenal ulcers but since prostaglandins tend to augment pain sensation, the pain typically experienced by patients suffering from these conditions during prostaglandin treatment is more severe than during the H2 blocking treatment modalities. Therefore, so far prostaglandins of the E type are mostly used prophylactically to prevent formation of gastric and/or duodenal ulcer during therapy with anti-inflammatory agents rather than to treat already established ulcers.
THE PRESENT INVENTION
We have now unexpectedly found that by certain modifications of the prostaglandin E molecule it is possible to eliminate its irritating effect on sensory nerves. It has moreover been found that such PGE-derivatives lacks a diarrheagenic effect.
The prostaglandin derivatives to be used according to the invention are 13,14-dihydro-derivatives of PGE, and especially of PGE.sub.2 in which the omega chain contains a ring structure, preferably a phenyl ring.
In copending patent application Ser. No. 469442 the general concept of modifying the omega chain of prostaglandins A, B, E and F, is disclosed. The derivatives were found to exhibit excellent properties for use in the treatment of glaucoma or ocular hypertension.
The derivatives to be used in a method for treating a person having duodenal or gastric ulcer, gastritis or related alimentary diseases have the general structure: ##STR1## wherein R is an alkyl chain with 1-10 carbon atoms, especially with 1-6 carbon atoms
RI is O or CH.sub.2 PA1 RII is H, OH, lower alkyl, preferably with 1-3 carbon atoms, halogen, preferably Cl, Br and F PA1 X is carbon chain with 1-9, preferably 1-6, and more specifically 2-6, such as 2, 3, 4, 5, or 6 atoms in the chain, optionally interrupted by one heteroatom O, N or S PA1 RIII is a ring structure selected from the group consisting of PA1 an aromatic heterocyclic group having 5-6 ring atoms, like thiazol, imidazole, pyrrolidine, thiopene and oxazole; or
a phenyl group which is unsubstituted or has one or more substituents selected from C1-C5 alkyl groups, C1-C4 alkoxy groups, trifluoromethyl groups, C1-C3 aliphatic acylamino groups, nitro groups, halogen atoms, and a phenyl group; or
a cycloalkane or a cycloalkene with 3-7 carbon atoms in the ring, optionally substituted with lower alkyl groups with 1-5 carbon atoms
In a presently preferred embodiment of the intention a prostaglandin derivative to be used according to this invention is a 13,14-dihydro-17-phenyl-18,19,20-trinor-PGE.sub.2 -alkyl ester, in which the alkyl chain has 1-10 carbon atoms, and especially 1-6 atoms, for instance methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl or benzyl esters.
The invention will in the following be illustrated with a preferred method for the synthesis of a suitable derivative and by comparative biological experiments.